The Relation of Total and Individual Fructose-containing Sugars With Incident Cardiometabolic Diseases: A Series of Systematic Reviews and Meta-analyses of Prospective Observational Studies

Background: Fructose has become a focus of intense concern regarding its links to the obesity epidemic and increasing burden of cardiometabolic disease. There have been dozens of editorials, commentaries, and letters in the scientific literature and numerous pieces in the lay and social media calling for efforts to restrict its intake and even regulate it like tobacco or alcohol. Uncontrolled ecological analyses which have linked increasing fructose intake with increasing obesity, diabetes, and hypertension rates and animal models of fructose induced metabolic syndrome and hypertension, which overfeed fructose at levels of exposure far beyond actual population levels of intake, have been used to underpin this debate. Evidence from well-adjusted prospective cohort studies also suggest a positive association between the consumption of sugar-sweetened beverages and increased energy consumption and weight gain. But not all meta-analyses of the available prospective cohort studies have supported this conclusion for SSBs, and no meta-analyses have investigated the effect of total fructose-containing sugars which also include grain and fruit sources on incident overweight/obesity, diabetes, metabolic syndrome, hypertension, gout, and cardiovascular disease. Despite the limitations in extrapolating from the available observational data and their inconsistency with data from controlled trials in humans (the highest level of evidence used in evidence based medicine) which do not show any adverse metabolic effects under isocaloric feeding conditions, the heart and diabetes associations have taken a risk reduction approach to added fructose-containing sugars, setting highly restrictive upper thresholds for their intake to achieve and maintain healthy body-weights and avoid adverse lipid effects.

Objective: To improve the evidence on which recommendations and public health policy are based, we will conduct a series of systematic reviews and meta-analyses of the role of fructose-containing sugars in the development of cardiometabolic disease in prospective cohort studies. A total of 5 analyses are proposed: (1)overweight/obesity, (2) diabetes/metabolic syndrome, (3) hypertension, (4) gout, and (5) coronary heart disease (CHD).

Design: The planning and conduct of the proposed meta-analyses will follow the Cochrane handbook for systematic reviews of interventions. The reporting will follow the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines.

Data sources. MEDLINE, EMBASE, CINAHL and The Cochrane Central Register of Controlled Trials (Clinical Trials; CENTRAL) will be searched using appropriate search terms, supplemented by manual, hand searches of bibliographies.

Study selection: We will include prospective cohort studies investigating the relation of fructose-containing (fructose, sucrose, and HFCS) sugars to incident overweight/obesity, diabetes, metabolic syndrome, hypertension, gout, and cardiovascular disease.